Inside Health

Expert Q & A

Nature, Nurture and Attention Deficit

By ALIYAH BARUCHIN

Susan Smalley, Ph.D., is a professor in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles, Semel Institute for Neuroscience and Human Behavior and director of its Mindful Awareness Research Center. Dr. Smalley’s work has a dual focus: the genetics of attention-deficit hyperactivity disorder and the use of techniques of mindfulness in promoting well-being.

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Q: Many people notice that attention-deficit hyperactivity disorder, or A.D.H.D., seems to run in families. Is it very strongly inherited?

A: It is; the heritability of A.D.H.D. is 76 percent.

Q: Does that mean that 76 percent of all cases of A.D.H.D. are inherited?

A: No — heritability is different: it’s looking at the variability in the population at a particular point in time. If you think about height and you lined everybody up in the population, you could see a nice, kind of a bell-shaped curve, with very tall people at one extreme and very short people at the other extreme, and the majority of people falling in this middle place, around the average. That bell-shaped curve is the distribution of variability of height in the population.

Now, if you could measure people’s genes that contribute to height, we know that 60 to 80 percent of the variability in height is due to genetic differences. That’s heritability — the proportion of the total variance that’s due to genes. How much of the variance in A.D.H.D. is due to genetics? That’s where that 76 percent comes from.

Q: So the heritability of A.D.H.D. rivals that of height? We typically think of height as being very strongly inherited.

A: The heritability of A.D.H.D. is very high; that’s a very high number, 76 percent. When we look at other psychiatric conditions — things like depression — it’s more on the order of 50 percent. Autism tends to be one of the highest; it’s around 90 percent.

Q: Have we located any of the specific genes that contribute to A.D.H.D.?

A: We’re still at the level of trying to find the genes that might play a role in A.D.H.D. That work has yielded several likely genes that are involved in A.D.H.D., but none of them has a big effect. We were saying 76 percent of the variance is genetic. These are genes that contribute to maybe 2 percent, 5 percent — very small, small amounts.

But it’s very likely that the genes that are involved in A.D.H.D. are going to be many, many more than we’ve identified to date, and a lot of research groups, including our own, have been actively looking throughout the whole genome for genes that might have a bigger role. It’s kind of like looking for a needle in a haystack. Those are the genome-wide approaches, genome-scan approaches, to A.D.H.D.

Q: How does the genome-scan approach work?

A: There are two approaches to searching for these genes. A candidate-gene approach is when you know a gene, and you go in and you directly say, “Does this gene contribute to A.D.H.D.?” You have to have the gene; you’ve got to know what it is and how to look at differences in that gene. That’s where we’ve found the handful that have played a role so far.

But the majority of discoveries for disease-gene relationships haven’t really emerged from that approach. They’re more often found by using the genome-wide approach — by saying, “O.K., there’re 30,000 genes in the genome. Let’s sample little pieces of DNA throughout the whole genome that we can study in pairs of siblings, for example, with A.D.H.D., or in relatives that we can study. Do they share a particular piece of DNA more often than you’d expect by chance?” If so, then the piece of DNA they share is going to be located really near the risk gene.

Using that approach, you don’t have a clue where the gene might be, but you actively search everywhere. And my analogy is, finding a gene is about equivalent to finding a contact lens at Disneyland — sort of the ratio of the size of the gene to the size of all your DNA, or the genome. Finding a contact lens in Disneyland: that would be pretty hard. But it wouldn’t be so hard if we had a really good map, and a technique for saying, “O.K., the chance that you’ve lost it in Space Mountain is much larger than the chance that you lost it on Tom Sawyer Island, right?”

Q: Does that type of map exist?

A: Yes. That’s what a genome-wide strategy does: it samples all [areas] across the whole Disneyland park with a grid, a map. You study people who have A.D.H.D., asking which pieces of DNA they have in common among the 300,000 pieces of DNA that span the whole genome. They can be used as a marker map, to study differences in the population. It helps us locate the likely candidate gene. You still don’t have the gene; you just know its location. Marker maps help you map the most likely position, in the whole genome, for a gene that contributes to A.D.H.D.